Proteasome allostery as a population shift between interchanging conformers
Bibliographic record
Abstract
Protein degradation plays a critical role in cellular homeostasis, in regulating the cell cycle, and in the generation of peptides that are used in the immune response. The 20S proteasome core particle (CP), a barrel-like structure consisting of four heptameric protein rings stacked axially on top of each other, is central to this process. CP function is controlled by activator complexes that bind 75 Å away from sites catalyzing proteolysis, and biochemical data are consistent with an allosteric mechanism by which binding is communicated to distal active sites. However, little structural evidence has emerged from the high-resolution images of the CP. Using methyl TROSY NMR spectroscopy, we demonstrate that in solution, the CP interconverts between multiple conformations whose relative populations are shifted on binding of the 11S activator or mutation of residues that contact activators. These conformers differ in contiguous regions of structure that connect activator binding to the CP active sites, and changes in their populations lead to differences in substrate proteolysis patterns. Moreover, various active site modifications result in conformational changes to the activator binding site by modulating the relative populations of these same CP conformers. This distribution is also affected by the binding of a small-molecule allosteric inhibitor of proteolysis, chloroquine, suggesting an important avenue in the development of therapeutics for proteasome inhibition.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".